The present invention relates to spirocyclic cyclohexane compounds, to methods for their production, to pharmaceutical compositions containing these compounds and to the use of spirocyclic cyclohexane compounds for producing pharmaceutical compositions.
The heptadecapeptide nociceptin is an endogenous ligand of the ORL1 (Opioid-Receptor-Like)-receptor (Meunier et al., Nature 377, 1995, p. 532-535), which belongs to the family of opioid receptors and is found in many regions of the brain and the spinal cord and has high affinity for the ORL1 receptor. The ORL1 receptor is homologous to the μ, κ and δ opioid receptors, and the amino acid sequence of the nociceptin peptide has a pronounced similarity to those of the known opioid peptides. The activation of the receptor induced by the nociceptin leads, via the coupling with Gi/o proteins to inhibition of adenylate cyclase (Meunier et al., Nature 377, 1995, p. 532-535).
After intercerebroventicular application, the nociceptin peptide exhibits pronociceptive and hyperalgesic activity in various animal models (Reinscheid et al., Science 270, 1995, p. 792-794). These findings can be explained as inhibition of stress-induced analgesia (Mogil et al., Neuroscience 75, 1996, p. 333-337). In this connection, anxiolytic activity of the nociceptin could also be demonstrated (Jenck et al., Proc. Natl. Acad. Sci. USA 94, 1997, 14854-14858).
On the other hand, an antinociceptive effect of nociceptin could also be demonstrated in various animal models, in particular after intrathecal application. Nociceptin has an antinociceptive effect in various pain models, for example in the tail flick test in mice (King et al., Neurosci. Lett., 223, 1997, 113-116). In models of neuropathic pain, an antinociceptive effect of nociceptin could also be detected, and was particularly beneficial since the effectiveness of nociceptin increases after axotomy of spinal nerves. This contrasts with conventional opioids, of which the effectiveness decreases under these conditions (Abdulla and Smith, J. Neurosci., 18, 1998, p. 9685-9694).
The ORL1 receptor is also involved in the regulation of further physiological and pathophysiological processes. These include inter alia learning and memory (Manabe et al., Nature, 394, 1997, p. 577-581), Hearing capacity (Nishi et al., EMBO J., 16, 1997, p. 1858-1864) and numerous further processes. A synopsis by Calo et al. (Br. J. Pharmacol. 129, 2000, 1261-1283) gives an overview of the indications or biological procedures, in which the ORL1-receptor plays a part or probably plays a part. Mentioned inter alia are: analgesics, stimulation and regulation of nutrient absorption, effect on μ-agonists such as morphine, treatment of withdrawal symptoms, reduction of the addiction potential of opioids, anxiolysis, modulation of motor activity, memory disorders, epilepsy; modulation of neurotransmitter release, in particular of glutamate, serotonin and dopamine, and therefore neurodegenerative diseases; influencing the cardiovascular system, triggering an erection, diuresis, anti-natriuresis, electrolyte balance, arterial blood pressure, water retention disorders, intestinal motility (diarrhoea), relaxation of the respiratory tract, micturation reflex (urinary incontinence). The use of agonists and antagonists as anoretics, analgesics (also when administered with opioids) or nootropics is also discussed.
The possible applications of compounds that bind to the ORL1 receptor and activate or inhibit it are correspondingly diverse. In addition to this one, however, opioid receptors such as the μ receptor, but also the other subtypes of these opioid receptors, namely δ and κ, play a significant part in the field of pain therapy and also the other aforementioned indications. It is accordingly desirable if the compound also has an effect on these opioid receptors.